1. Field of the Invention
The present invention relates to a series of substituted 3-aminopropane phosphinic acid derivatives. More specifically, the present invention relates to a series of 3-amino-peptidyl-2-hydroxypropane-cyclohexylmethyl phosphinic acid derivatives. This invention also relates to methods of making these compounds. The compounds of this invention are transformed in vivo into biologically active compounds and are, therefore, useful as pharmaceutical agents, especially in the treatment and/or prevention of a variety of diseases including diseases associated with the central nervous system.
2. Description of the Art
U.S. Pat. No. 5,190,933 discloses certain substituted propane phosphinic compounds having therapeutic utility in treating various disorders including cognition and memory disorders, anxiety and depression. However, a problem posed by these compounds is their poor bioabsorption. It has also been reported in the literature that certain compounds such as bisphosphonates exhibit poor absorption from the GI tract. In fact, only one percent of the oral dose is absorbed. As a result, a series of peptidyl prodrugs of these bisphosphonates have been made and shown to improve the drug absorption. See, Ezra, et al., J. Med. Chem. 2000, 43, 3641.
It has also been reported that human peptide transporter, hPepT1, situated in the small intestine, may be exploited among others to increase absorption of drugs or model drugs by attaching them to a dipeptide. A synthetic protocol has also been suggested to attach a dipeptide to model drugs containing a hydroxy group. See Friedrichsen et al., Eur. J. Pharm. 2001, 14, 13.
International Publication No. WO99/51613 discloses prodrugs of phosphorus containing pharmaceuticals. The compounds disclosed therein are derived from a phosphonate, phosphinate or phosphoryl function having at least two functional moieties. These compounds have been claimed to exhibit enhanced bioavailability or other pharmacokinetic performance relative to the parent drug.
All of the references described herein are incorporated herein by reference in their entirety.
However, there have been no reports in the literature that prodrugs of above mentioned propane phosphinic compounds can also be similarly made. Further, it has not been reported that peptidyl prodrugs, especially, mono-, di- and tri-peptidyl derivatives of 3-amino-2-hydroxypropane phosphinic compounds may offer improved bioabsorption properties.
Accordingly, it is an object of this invention to provide a series of 3-amino-peptidyl-2-hydroxypropane-cyclohexylmethyl phosphinic acid derivatives that exhibit improved bioavailability relative to the parent compound.
It is also an object of this invention to provide processes for the preparation of 3-amino-peptidyl-2-hydroxypropane-cyclohexylmethyl phosphinic acid derivatives as disclosed herein.
Other objects and further scope of the applicability of the present invention will become apparent from the detailed description that follows.